DNA damage and repair Flashcards
What are human progeria syndromes?
Mutations lead to increased DNA damage
and/or failure to repair damage this then leads to premature ageing.
How much DNA damage is present in each cell?
19,200
How much DNA damage is there in the whole body?
710,000
What are the sources of DNA damage?
Metabolism
UV light
Ionising radiation
DNA synthesis
Environmental mutagens
What are ROS?
Reactive oxygen species
Where do the reactive oxygen species come from?
Produced by every cell during metabolism in the mitochondria.
What is the problem with 8-oxodG being in the body??
Causes pairing so bad DNA replication.
How does UV lead to DNA damage?
Produces pyrimidine dimers in exposed tissue, these replicate single strand breaks which cause double strand breaks which are toxic.
How does ionising radiation cause DNA damage?
Directly causes double-strand breaks which is the most toxic damage?
What is a manmade ionising radiation?
Cancer treatment
What wave range is UV light?
300nm
Where does ionising radiation come from?
Radon
Cosmic rats
Radionucleotides
How does DNA synthesis lead to DNA damage?
It is highly error-prone and DNA strand breaks occur.
How many mistakes occur per replicated genome?
600
What are environmental mutagens?
Food
Water
Air-borne
Smoking
Industrial
How do cells cope with DNA damage?
DNA repair
They prevent the replication of damaged DNA, apoptosis kills damaged cells.
What is MGMT?
O-6-methylguanine-DNA which is a DNA damage repair protein.
Why isn’t MGMT an enzyme?
It can only function once.
What is the direct role of MGMT?
Repairs methylation damage.
What does global genome NER mean?
Involving the whole genome.
What does T-coupled NER mean?
Involving the transcription complex part of the genome.
What is NER?
Nucleotide excision repair
What is nucleotide excision repair?
The primary mechanism for repair of UV induced
damage (XP).
What is the difference between the global NER and t-coupled NER pathways?
Proteins which recognise damage.
Which proteins recognise damage during t-coupled NER pathways?
CSA and CSB.
Which proteins recognise damage during global NER pathways?
XB/C
What is C syndrome?
Damage to CSA/B proteins which recognise the damage in t-coupled NER.
What does C syndrome lead to?
TF2H complex abnormalities (transcription factors).
What is Xeroderma pigmentosum?
Leads to XB mutations.
What is Base excision repair?
The main mechanism for repair of oxidative
damage. (Also alkylation, deamination,
depurination/depyrimidination)
What kinds of base excision repair exists?
Short and long patch.
When is base excision repair used?
During single base damage.
What is damage recognised by during base excision repair?
DNA glycosylase (OOG1).
How was it proved that DNA glycosylase is used for recognition in base excision repair?
Using knockout mice.
What is mismatch repair?
The primary mechanism for recognition of DNA mismatches arising during DNA replication.
What kinds of mismatch repair occurs during DNA replication?
– Single base mismatches
– Small insertion/deletions
Why is mismatch repair important during cancer?
Recognises chemically-induced DNA damage, including important chemo-therapeutics.
What is the risk with mutations to the mismatch repair pathway?
Mutations in this pathway are associated with
familial colon cancer
Why are double strand breaks the most toxic double-strand lesions?
Can lead to chromosome aberrations.
What are the 2 different mechanisms of double-strand break repair?
– Non-homologous end joining.
– Homologous recombination.
What is the problem with non-homologous end joining?
It is highly error-prone, if ends are broken in the same place deletion occurs (however this prevents cancer).
What is the positive of homologous recombination?
It is error free.
When does homologous recombination ocuur?
Late S/G2.
What is the most common solution to double stranded breaks?
Apoptosis.
